While only the 31st most common cause of cancer, pancreatic cancer is the fourth most common cause of cancer-related death in the US. Patients typically present with advanced disease that is notoriously refractory to chemotherapy. Indeed, the 5 year survival rate is below 5%. Radical resection with adjuvant chemotherapy is potentially curative, but less than 15% of patients qualify for resection (local disease). Despite decades of research, meaningful advancements in the therapeutic intervention of PDAC have been largely absent. In other oncologic indications, there have been several recent clinical successes in targeted tumor delivery of therapeutic payloads, and the first clinical product will likely be approved in the US in 2011. Therefore, the overall goal of this proposal is to develop a molecularly targeted nanoparticle based platform capable of being loaded with and targeting efficacious chemotherapies directly to pancreatic tumors. Recently, in a screen of cell surface markers of pancreatic cancer, we have identified a highly specific and novel cell surface biomarker, Plectin-1. Plectin-1 is normally a cytoplasmic protein predominantly expressed in the muscle and skin. But it is aberrantly surface expressed in in early, precancerous lesions as well as in 100% of human pancreatic tumors and metastatic lesions tested to date (N>100). Plectin-1 is up-regulated in a number of additional cancers including lung, ovarian and esophageal. A novel high-affinity and specific plectin-1 targeting peptide (PTP) that internalizes upon binding has been identified and thoroughly characterized. The proposed work has the long-term objective to develop a flexible therapeutic payload delivery platform capable of targeting to cells expressing the biomarker plectin-1, such as pancreatic tumors. Outcomes from these studies will provide feasibility data on the ability to target cell- killing agents to various pancreatic cncer cell lines in vitro and in vivo. A lead product will be identified for advancing this work to a phae II effort focusing on product optimization, preclinical enabling toxicology and IND filing. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop a new drug delivery system that targets to a novel cancer tag for use in treating pancreatic cancer and other cancers. We will do this by making small particles that are capable of holding drugs and are targeted to the cancer through the use of tags that identify the cancer. The developed targeted drug delivery system will ultimately be used for delivery of numerous cell-killing agents specifically to cancer cells, potentially extending and improving cancer patient's lives.